The development of new blood vessels, or angiogenesis, is essential for the growth and metastasis of most solid tumors. Targeting the endothelial cells that line tumor blood vessels is a promising anticancer strategy. We have recently identified several cell surface tumor endothelial markers (TEMs) that are conserved in both mouse and humans and that represent potentially useful targets for anticancer therapy. To determine whether these TEMs are in fact useful targets, we will begin translational studies using transplantable tumor models in mice. To target cell surface TEMs, we will develop antibodies recognize native TEM proteins on the cell surface of both mouse and human tumor vessels. Initial studies will involve screening the antibodies for their ability to bind live cells which express the target TEM. Whenever possible, secondary screens to identify neutralizing antibodies will be employed. Subsequently, antibodies with the best sensitivity and specificity will be tested for their tumoricidal properties in preclinical mouse models and, if necessary, may be conjugated to small molecular weight drugs to generate antibody-drug conjugates. CAR T cells will also be generated. Antibodies will also be tested for their ability to detect soluble TEMs in the blood. Combinations of our novel anti-angiogenics with conventional anti-cancer agents will also be tested.